About 9 per cent of the global population suffers from chronic kidney disease (CKD). Not only does CKD impair renal function, but it has long been linked to an elevated risk of cardiovascular disease, according to a World Burden of Disease Study 2017.

Researchers led by Kyushu University have discovered an underlying molecular pathway that helps explain how chronic kidney disease causes heart failure in a new study that could aid in the development of therapeutic medications to lessen these cardiac problems.

The researchers discovered that a significant cause is the malfunctioning of a type of white blood cell called monocyte, which they studied in mice. Increased amounts of vitamin A and its binding protein—a frequent indication of chronic kidney disease—cause the malfunctioning, which disrupts a well-known genetic pathway: the circadian clock.

Human Anatomy

The Circadian Clock

One of the most important biological activities in living creatures is the circadian clock. The route is commonly thought to influence our sleep habits. The circadian clock, on the other hand, plays a far larger role, influencing blood pressure, metabolic rate, and even hormone levels. In fact, the circadian clock has a direct influence on roughly 10% of our genes.

"We found that mice with a mutated Clock gene--one of the main regulators of the circadian clock--have decreased symptoms of heart problems related to chronic kidney disease, despite having high blood pressure," reveals Yuya Yoshida, one of the primary research authors, in the journal Nature Communications.

To find the underlying source of this protective effect, the researchers looked for changes in genes linked to Clock and renal disease.

Naoya Matsunaga, another research author, states, "Our investigation led us to find that a protein called 'G protein-coupled receptor 68,' or GPR68, produced in monocytes was playing a key role. GPR68 is known to increase the production of proteins that cause inflammation, and more importantly, it is regulated by the Clock gene"

Human kidney

Elevated levels of vitamin A and its binding protein, two molecules that are normally tightly regulated, are one indicator of renal disease. The researchers discovered that this increase affects the normal operation of the circadian clock in monocytes, causing them to overexpress GPR68.

These monocytes with high GPR68 expression then invade the heart, causing inflammatory responses and fibrosis. Because there is no Clock gene to make GPR68, mice with faulty Clock genes have less severe CKD-induced heart issues.

Ohdo says, "Our study reveals a previously unknown role of monocytic clock genes in CKD-induced heart failure,the findings will help us develop therapeutic drugs such as ones targeting GPR68. We also can investigate better treatments for abnormal vitamin A accumulation in the blood."